Pathogenesis of rhinitis Eifan, A. O.; Durham, S. R.
Clinical and experimental allergy,
September 2016, Volume:
46, Issue:
9
Journal Article
Peer reviewed
Summary
Rhinitis is a heterogeneous condition that has been associated with inflammatory responses as in allergic rhinitis but can also occur in the absence of inflammation such as in so‐called ...idiopathic (previously ‘vasomotor’) rhinitis. Allergic rhinitis affects approximately one in four of the population of westernized countries and is characterized by typical symptoms of nasal itching, sneezing, watery discharge and congestion. The intention of this review is to illustrate key concepts of the pathogenesis of rhinitis. Imbalance in innate and adaptive immunity together with environmental factors is likely to play major roles. In allergic rhinitis, initial allergen exposure and sensitization involves antigen‐presenting cells, T and B lymphocytes and results in the generation of allergen‐specific T cells and allergen‐specific IgE antibodies. On re‐exposure to relevant allergens, cross‐linking of IgE on mast cells results in the release of mediators of hypersensitivity such as histamine and immediate nasal symptoms. Within hours, there is an infiltration by inflammatory cells, particularly Th2 T lymphocytes, eosinophils and basophils into nasal mucosal tissue that results in the late‐phase allergic response. Evidence for nasal priming and whether or not remodelling may be a feature of allergic rhinitis will be reviewed. The occurrence of so‐called local allergic rhinitis in the absence of systemic IgE will be discussed. Non‐allergic (non‐IgE‐mediated) rhinitis will be considered in the context of inflammatory and non‐inflammatory disorders.
Allergen immunotherapy (AIT) has been thoroughly documented in randomized controlled trials (RCTs). It is the only immune-modifying and causal treatment available for patients suffering from ...IgE-mediated diseases such as allergic rhinoconjunctivitis, allergic asthma and insect sting allergy. However, there is a high degree of clinical and methodological heterogeneity among the endpoints in clinical studies on AIT, for both subcutaneous and sublingual immunotherapy (SCIT and SLIT). At present, there are no commonly accepted standards for defining the optimal outcome parameters to be used for both primary and secondary endpoints.
As elaborated by a Task Force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) Immunotherapy Interest Group, this Position Paper evaluates the currently used outcome parameters in different RCTs and also aims to provide recommendations for the optimal endpoints in future AIT trials for allergic rhinoconjunctivitis.
Based on a thorough literature review, the TF members have outlined recommendations for nine domains of clinical outcome measures. As the primary outcome, the TF recommends a homogeneous combined symptom and medication score (CSMS) as a simple and standardized method that balances both symptoms and the need for antiallergic medication in an equally weighted manner. All outcomes, grouped into nine domains, are reviewed.
A standardized and globally harmonized method for analysing the clinical efficacy of AIT products in RCTs is required. The EAACI TF highlights the CSMS as the primary endpoint for future RCTs in AIT for allergic rhinoconjunctivitis.
Summary
This guidance for the management of patients with allergic and non‐allergic rhinitis has been prepared by the Standards of Care Committee (SOCC) of the British Society for Allergy and ...Clinical Immunology (BSACI). The guideline is based on evidence as well as on expert opinion and is for use by both adult physicians and paediatricians practicing in allergy. The recommendations are evidence graded. During the development of these guidelines, all BSACI members were included in the consultation process using a web‐based system. Their comments and suggestions were carefully considered by the SOCC. Where evidence was lacking, consensus was reached by the experts on the committee. Included in this guideline are clinical classification of rhinitis, aetiology, diagnosis, investigations and management including subcutaneous and sublingual immunotherapy. There are also special sections for children, co‐morbid associations and pregnancy. Finally, we have made recommendations for potential areas of future research.
Allergic rhinitis is a common condition which, at its most severe, can significantly impair quality of life despite optimal treatment with antihistamines and topical nasal corticosteroids. Allergen ...injection immunotherapy significantly reduces symptoms and medication requirements in allergic rhinitis but its use is limited by the possibility of severe systemic reactions. There has therefore been considerable interest in alternative routes for delivery of allergen immunotherapy, particularly the sublingual route. The objective was to evaluate the efficacy of sublingual immunotherapy (SLIT), compared with placebo, for reductions in symptoms and medication requirements. The Cochrane Controlled Clinical Trials Register, MEDLINE (1966–2002), EMBASE (1974–2002) and Scisearch were searched, up to September 2002, using the terms (Rhin* OR hay fever) AND (immunotherap* OR desensiti*ation) AND (sublingual). All studies identified by the searches were assessed by the reviewers to identify Randomized Controlled Trials involving participants with symptoms of allergic rhinitis and proven allergen sensitivity, treated with SLIT or corresponding placebo. Data from identified studies was ed onto a standard extraction sheet and subsequently entered into RevMan 4.1. Analysis was performed by the method of standardized mean differences (SMD) using a random effects model. P‐values < 0.05 were considered statistically significant. Subgroup analyses were performed according to the type of allergen administered, the age of participants and the duration of treatment. Twenty‐two trials involving 979 patients, were included. There were six trials of SLIT for house dust mite allergy, five for grass pollen, five for parietaria, two for olive and one each for, ragweed, cat, tree and cupressus. Five studies enrolled exclusively children. Seventeen studies administered the allergen by sublingual drops subsequently swallowed, three by drops subsequently spat out and two by sublingual tablets. Eight studies involved treatment for less than 6 months, 10 studies for 6–12 months and four studies for greater than 12 months. All included studies were double‐blind placebo‐controlled trials of parallell group design. Concealment of treatment allocation was considered adequate in all studies and the use of identical placebo preparations was almost universal. There was significant heterogeneity, most likely due to widely differing scoring systems between studies, for most comparisons. Overall there was a significant reduction in both symptoms (SMD −0.42, 95% confidence interval −0.69 to −0.15; P = 0.002) and medication requirements SMD −0.43 (−0.63, −0.23); P = 0.00003 following immunotherapy. Subgroup analyses failed to identify a disproportionate benefit of treatment according to the allergen administered. There was no significant reduction in symptoms and medication scores in those studies involving only children but total numbers of participants was too small to make this a reliable conclusion. Increasing duration of treatment does not clearly increase efficacy. The total dose of allergen administered may be important but insufficient data was available to analyse this factor.
Background
Allergen immunotherapy (AIT) is an effective treatment for allergic rhinoconjunctivitis (AR) with or without asthma. It is important to note that due to the complex interaction between ...patient, allergy triggers, symptomatology and vaccines used for AIT, some patients do not respond optimally to the treatment. Furthermore, there are no validated or generally accepted candidate biomarkers that are predictive of the clinical response to AIT. Clinical management of patients receiving AIT and efficacy in randomised controlled trials for drug development could be enhanced by predictive biomarkers.
Method
The EAACI taskforce reviewed all candidate biomarkers used in clinical trials of AR patients with/without asthma in a literature review. Biomarkers were grouped into seven domains: (i) IgE (total IgE, specific IgE and sIgE/Total IgE ratio), (ii) IgG‐subclasses (sIgG1, sIgG4 including SIgE/IgG4 ratio), (iii) Serum inhibitory activity for IgE (IgE‐FAB and IgE‐BF), (iv) Basophil activation, (v) Cytokines and Chemokines, (vi) Cellular markers (T regulatory cells, B regulatory cells and dendritic cells) and (vii) In vivo biomarkers (including provocation tests?).
Results
All biomarkers were reviewed in the light of their potential advantages as well as their respective drawbacks. Unmet needs and specific recommendations on all seven domains were addressed.
Conclusions
It is recommended to explore the use of allergen‐specific IgG4 as a biomarker for compliance. sIgE/tIgE and IgE‐FAB are considered as potential surrogate candidate biomarkers. Cytokine/chemokines and cellular reponses provided insight into the mechanisms of AIT. More studies for confirmation and interpretation of the possible association with the clinical response to AIT are needed.
Summary
Allergen immunotherapy is allergen‐specific, allergen dose‐ and time‐dependent and is associated with long‐term clinical and immunological tolerance that persists for years after ...discontinuation. Successful immunotherapy is accompanied by the suppression of numbers of T‐helper 2 (Th2) effector cells, eosinophils, basophils, c‐kit+mast cells and neutrophils infiltration in target organs, induction of IL‐10 and/or TGF‐β+Treg cells and increases in ‘protective’ non‐inflammatory blocking antibodies, particularly IgG4 and IgA2 subclasses with inhibitory activity. These events are accompanied by a reduction and/or a redirection of underlying antigen‐specific Th2‐type T cell‐driven hypersensitivity to the allergen(s) used for therapy. This suppression occurs within weeks or months as a consequence of the appearance of a population of regulatory T cells that exert their effects by mechanisms involving cell–cell contact, but also by the release of cytokines such as IL‐10 (increases IgG4) and TGF‐β (increases specific IgA). The more delayed‐in‐time appearance of antigen‐specific T‐helper 1 responses and alternative mechanisms such as Th2 cell anergy and/or apoptosis may also be involved. The mechanisms of sublingual immunotherapy are similar to those following a subcutaneous administration of allergen, whereas it is likely that additional events following antigen presentation in the sublingual mucosa and regional lymph nodes are involved. These insights have resulted in novel approaches and portend future biomarkers that may be surrogate or predictive of the clinical response to treatment.
Cite this as: M. H. Shamji and S. R. Durham, Clinical & Experimental Allergy, 2011 (41) 1235–1246.
Background
Clinical efficacy of pollen allergen immunotherapy (AIT) has been broadly documented in randomized controlled trials. The underlying clinical endpoints are analysed in seasonal time ...periods predefined based on the background pollen concentration. However, any validated or generally accepted definition from academia or regulatory authorities for this relevant pollen exposure intensity or period of time (season) is currently not available. Therefore, this Task Force initiative of the European Academy of Allergy and Clinical Immunology (EAACI) aimed to propose definitions based on expert consensus.
Methods
A Task Force of the Immunotherapy and Aerobiology and Pollution Interest Groups of the EAACI reviewed the literature on pollen exposure in the context of defining relevant time intervals for evaluation of efficacy in AIT trials. Underlying principles in measuring pollen exposure and associated methodological problems and limitations were considered to achieve a consensus.
Results
The Task Force achieved a comprehensive position in defining pollen exposure times for different pollen types. Definitions are presented for ‘pollen season’, ‘high pollen season’ (or ‘peak pollen period’) and ‘high pollen days’.
Conclusion
This EAACI position paper provides definitions of pollen exposures for different pollen types for use in AIT trials. Their validity as standards remains to be tested in future studies.
This is an updated guideline for the diagnosis and management of allergic and non‐allergic rhinitis, first published in 2007. It was produced by the Standards of Care Committee of the British Society ...of Allergy and Clinical Immunology, using accredited methods. Allergic rhinitis is common and affects 10–15% of children and 26% of adults in the UK, it affects quality of life, school and work attendance, and is a risk factor for development of asthma. Allergic rhinitis is diagnosed by history and examination, supported by specific allergy tests. Topical nasal corticosteroids are the treatment of choice for moderate to severe disease. Combination therapy with intranasal corticosteroid plus intranasal antihistamine is more effective than either alone and provides second line treatment for those with rhinitis poorly controlled on monotherapy. Immunotherapy is highly effective when the specific allergen is the responsible driver for the symptoms. Treatment of rhinitis is associated with benefits for asthma. Non‐allergic rhinitis also is a risk factor for the development of asthma and may be eosinophilic and steroid‐responsive or neurogenic and non‐ inflammatory. Non‐allergic rhinitis may be a presenting complaint for systemic disorders such as granulomatous or eosinophilic polyangiitis, and sarcoidoisis. Infective rhinitis can be caused by viruses, and less commonly by bacteria, fungi and protozoa.
The coherent elastic scattering of neutrinos off nuclei has eluded detection for four decades, even though its predicted cross section is by far the largest of all low-energy neutrino couplings. This ...mode of interaction offers new opportunities to study neutrino properties and leads to a miniaturization of detector size, with potential technological applications. We observed this process at a 6.7σ̃ confidence level, using a low-background, 14.6-kilogram CsINa scintillator exposed to the neutrino emissions from the Spallation Neutron Source at Oak Ridge National Laboratory. Characteristic signatures in energy and time, predicted by the standard model for this process, were observed in high signal-to-background conditions. Improved constraints on nonstandard neutrino interactions with quarks are derived from this initial data set.
To measure the prevalence of allergic rhinitis among European adults and the proportion of undiagnosed subjects, a two-step, cross-sectional, population-based survey in Belgium, France, Germany, ...Italy, Spain, and the UK was undertaken. Step one of the study involved screening for allergic rhinitis by telephone interview, based on history of symptoms and/or self-awareness of the condition. Step two undertook confirmation of allergic rhinitis in a subset of the subjects screened positive; this was performed by a clinical diagnosis conducted in three to five clinical centres per country, including specific immunoglobulin E tests and a disease-specific questionnaire. A total of 9,646 telephone interviews were conducted between February and April 2001. Self-awareness of allergic rhinitis was reported by 19% of the subjects. Physician-based diagnosis of allergic rhinitis was reported by 13% of the subjects. In step two, 725 clinical assessments were conducted between May and August 2001. A total of 411 of patients, who underwent step two, had investigator-confirmed allergic rhinitis. Among patients with investigator-confirmed allergic rhinitis, 45% had not reported a previous diagnosis by a physician. Prevalence of subjects with clinically confirmable allergic rhinitis estimated by combining step one and step two data ranged from 17% in Italy to 29% in Belgium with an overall value of 23%. This large-scale study confirms that allergic rhinitis has a high prevalence in western Europe and is frequently undiagnosed.
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